Med Clin N Am 92 (2008) 12271237

Prescribing Medications Safely During Pregnancy

William F. Rayburn, MD, MBA1,*, Adanna C. Amanze, MD2
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, 4th Floor, Ambulatory Care Center, 2211 Lomas Blvd. NE, Albuquerque NM 87106, USA

Medication use has changed among women of reproductive age in the United States. New products are being marketed directly to the consumer, increased concerns about safety and ecacy are apparent, public education has increased, and more prescription medications have been granted nonprescription status by the US Food and Drug Administration (FDA). Reproductive-age women increasingly are relied on to provide their internist or other primary health care provider with an accurate description of drugs they use. Although not widely practiced, drug regimens for chronic illnesses are best assessed and altered in the preconception period. Pregnancy is being diagnosed earlier because of the widespread availability of sensitive, over-the-counter home pregnancy tests. Unfortunately, because risks from many medications when taken during pregnancy are often unknown, there may be either a voluntary or involuntary cessation or an underreporting of medications. Most internists and their patients adopt a conservative approach to medication use during pregnancy, especially in the rst trimester. This article oers internists practical guidelines for prescribing medications when pregnancy is either anticipated or already discovered. Those medications studied most during human pregnancy and believed to pose the least risk are discussed along with limitations in knowledge when
* Corresponding author. Department of Obstetrics and Gynecology, MSC 10 5580, 1 University of New Mexico, Albuquerque NM 87131-0001. 1 Having a pharmacology background, he is the author of many studies reporting drug trials during pregnancy and of several texts dealing with drug therapy during pregnancy. 2 Before her subspecialty training, she was an active practitioner of general obstetrics and gynecology. E-mail address: wrayburn@salud.unm.edu (W.F. Rayburn). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.006 medical.theclinics.com

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considering which medication is safest. Strategies are proposed to counsel patients who require a specic medication and desire to become or already are pregnant. Prenatal medications Medications commonly taken prenatally include vitamins, iron preparations, calcium, analgesics, antibiotics, and antacids. Over-the-counter drugs account for approximately half of the medications, and acetaminophen remains the most commonly taken medication during pregnancy. Antibiotics are the most commonly prescribed drugs. Although tobacco, alcohol, and illicit substance use tends to decrease as pregnancy progresses, prescription medications are taken the same or more often during gestation. According to our experience, the mean number of medications consumed during the second and third trimesters, 3.3 and 4.1 respectively, is signicantly higher than the number (2.6) taken before pregnancy [1]. Given the abundance of medications available, it is unclear why there is a paucity of scientic information about their potential adverse eects on pregnancy. Risks and experience during pregnancy with new drugs are usually not well explored. As a result, practitioners often rely on older drugs during gestation because a larger body of information has been reported about them. These older medications may not be preferred after patients deliver. Special considerations during pregnancy Conrmation of pregnancy and accurate gestational dating are critical in determining susceptibilities. In utero exposure to a drug may be divided into three periods of fetal development: (1) ovum, from fertilization to implantation, (2) embryo, from the second through the eighth week, and (3) fetus, from the eighth completed week until delivery. An all or none eect (spontaneous abortion or not) is believed to result from exposure during the rstdor ovumdperiod. The second period, or embryo, encompasses the most critical time with respect to structural malformations, because it involves organogenesis. Any specic harmful eect relates to the timing and duration of drug exposure during this relatively brief but critical time of development. Drug absorption is not signicantly aected by pregnancy, but serum concentrations of albumin for drug binding are lower than when nonpregnant. Pharmacokinetic changes during pregnancy include a higher volume of distribution, lower maximum plasma concentration, lower steady serum state concentration, shorter plasma half-life, and higher clearance rate [2]. Virtually all drugs and their end products cross the placenta, with unbound concentrations of the drug being similar or, with chronic therapy, sometimes higher in fetal than maternal serum. A few drugs have a high molecular weight that prohibits transplacental passage in signicant amounts (eg, glyburide, interferon, thyroid supplements, and insulin).

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Despite being infrequent, detrimental eects may occur with certain drugs when taken beyond the rst 8 weeks of organogenesis. Cells continue to divide in the hematologic, reproductive, and central nervous systems. Few medications are implicated in restricting fetal growth or reducing organ size. There is minimal or no consistent information in humans about longterm eects, such as learning or behavior problems (functional teratogenesis), that may result from chronic prenatal exposure to a certain medication. Individual susceptibility is also dose dependent. Fetal risk to a constant dose of a medication may not be obvious in a small sample of cases but could be biologically signicant in a larger population. An increase in the daily dose of certain medications (eg, anticonvulsants, insulin, or thyroid supplementation) may be necessary during pregnancy to maintain serum concentrations in a therapeutic nonpregnant range. The only drugs suspected of prolonging gestation are the b-adrenergics, which stimulate uterine-relaxing b2-agonist receptors. No drug is known to directly shorten gestation, although a few have been questioned, including ergotamine and b-adrenergic blockers. Problems with studies in humans and animals All medications to be approved by the FDA must undergo animal studies to determine possible teratogenic eects. Animals used to study alterations on the fetus include rodents (fertility, birth defects, birth weights, behavior), rabbits (birth defects), baboons (uterine blood ow), and sheep (uterine blood ow, maternal and fetal cardiovascular eects, fetal hypoxia and acidosis). Doses are often much higher than typically used (per body weight or surface area) to test the systems for any possible detrimental reproductive harm. Although such studies may be helpful, if ndings indicate no additional risk, their results do not reliably predict the human response. Few medications are linked with abnormal fetal development. Major structural defects are apparent at birth in approximately 3% of all pregnancies and approximately 4.5% of all children by 5 years of age [2]. A cause or proposed mechanism for the defect can be determined in less than half of cases. Expert consensus on the safety of such agents often does not exist and may be impossible to achieve. In addition to the period of fetal development and the dose of the medication, other factors to consider when determining fetal risk include the exact identity of the medication, duration of therapy, underlying illness, other drugs, and the genetic susceptibility of the mother and fetus (eg, nicotine and cleft palate). Conclusions from human studies about birth defects must be interpreted cautiously. Results of retrospective and uncontrolled studies and individual case reports or small series may overestimate the fetal risk to a specic drug or a combination of medications. Case reports do not establish causation. Dierentiating between risks of a specic drug and hazards from a maternal illness can be dicult in explaining an unfavorable pregnancy outcome (eg,

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stillbirth: enoxaparin versus thrombophilia; fetal growth restriction: azathioprine versus underlying illness, b-blocker versus hypertension; spontaneous abortion: bupropion versus cigarette smoking; fetal distress: cholesyramine versus cholestasis). It is necessary to distinguish between the natural prevalence ratedthe rate at which the defect occurs in a populationdand the additional risk potentially attributable to a drug. Studies of large populations are required, yet usually unattainable, to determine the relative risk from specic potential teratogens. Assessing neurobehavioral eects from in utero exposure to centrally acting drugs is dicult, especially beyond the immediate neonatal period. The dose, osprings age and gender, and behavior test system must be considered. Doses in animals are often so high as to cause a toxic eect and result in adverse events in ospring.

Counseling the expectant mother In conjunction with an obstetrician, counseling before or during pregnancy about continuing or beginning a medication should be undertaken in an open, supportive, and informative manner. Most conditions involve drug exposures at low levels of relative and absolute risks. Strategies for prescribing medications in pregnancy are summarized in Box 1. Examples of questions for internists to ask about prenatal exposure to a medication are listed in Box 2. A detailed fetal ultrasound examination is often

Box 1. Strategies for prescribing medications during pregnancy (examples shown in parentheses)  Avoid multiple medications if possible and choose those that are safe (anticonvulsants, antihypertensives)  Determine what is the best method to monitor therapy (asthma: peak ow meters; hypertension: portable blood pressure monitors; diabetes: glucometers)  The healthiest mother is most likely to deliver the healthiest infant  Focus on the underlying disorder, not on the drug alone, to explain any additional risk to the fetus (hypertension and fetal growth restriction, seizures and childhood seizures, systemic lupus and fetal growth restriction)  Only a few drugs are clearly linked with specic birth defects (phenytoin, warfarin, alcohol, methotrexate, diethystilbestrol, cis retinoic acid, valproic acid, carbamazepine)  Experience with rst-trimester exposure for any drug is often too limited in humans to be considered safe

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Box 2. Examples of questions to ask about prenatal exposure to a medication      WHEN was the medication taken? WHY was the medication taken? HOW long was the medication taken? WHAT other drugs or substances were taken? WHERE do I nd more information?

recommended to accurately date the pregnancy and, if possible, screen for any structural defects. Further methods of early fetal evaluation, such as screening tools for aneuploidy in the rst and second trimester, are not predictive of direct eects from drugs. Many sources of information about potential teratogens are available as publications [35]. Table 1 lists references of computerized databases on teratogenic information about specic drugs. We nd the Reprotox reference [6] to be most helpful. To avoid liability, pharmaceutical manufacturers do not encourage prescribing their drugs during pregnancy unless the benet outweighs the risk. Marketing of a medication for specic use during pregnancy is unrealistic from the business perspective, because it requires much investment in time and cost to conduct research on a vulnerable population that is limited in number. Examples of standard statements in the Physicians Desk Reference about any medication include the following:
Reproductive studies, performed in rats and mice at maternally toxic dose levels, revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. As animal reproduction studies are not always predictive of human response, (name of medication) should be used during pregnancy only if clearly needed.

These statements are inconclusive and redirect attention to the obstetrician or internist for prescription decision making.
Table 1 Examples of references of databases on teratogenic information Organization Web site

National Library of Medicine www.nlm.nih.gov Organization of Teratogen Information Services www.otis.pregnancy.org Pharmaceutical companies www.pharmacy.org/company.html Poison control centers www.poison-control.com Pregnancy exposure registries www.fda.gov/womens/registries/default.htm Reproductive toxicology center http://reprotox.org Physicians Desk Reference http://www.pdr.net/login/Login.aspx

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Table 2 Examples of rst-line, second-line, and contraindicated agents in treating medical illnesses during pregnancy Drugs/medical illnesses Analgesics Antithyroid Antiacne First-line agents Acetaminophen Propylthiouracil Benzoyl peroxide Topical clindamycin Topical erythromycin Topical metronidazole Adenosine B-adrenergic blockers Calcium channel blockers Digoxin b2 agonist Inhaled corticosterioids Penicillins Cephalosporins Macrolides Second-line agents Opioids Methimazole Contraindicated NSAIDs O 48 hours I-131 Isotretinoin

Antiarrhythmics

Quninidine Amiodarone Flecainide

Antiasthmatics

Antibacterials

Anticoagulants

Anticonvulsants

Heparin Low molecular weight heparin Lamotrigine Gabapentin

Oral corticosterioids Anticholinergic agents Methylxanthines Leukotriene modiers Sulfonamides Tetracycline Trimethoprim Doxycycline Nitrofuratoin Quinolones Metronidazole Gentamycin Clindamycin Warfarin

Antidepressants

Antidiabetic Antidiarrheal Antiemetics

Antifungals Antihypertensives

Selective serotonin reuptake inhibitors Tricyclic antidepressants Insulin Glyburide Loperamide Pyridoxine Doxylamine with pyridoxine Antacids Topical imidazole Methyldopa Labetalol Nifedipine Corticosteroids

Valproate Carbamazepine Phenytoin Barbiturates Wellbutrin Cymbalta Benzodiazepines Metformin Kaopectate Promethazine Metoclopracamide Ondansetron Nystatin Fluconazole Propranolol Atenolol Diuretics Hydralazine

ACE inhibitors

Anti-inammatory

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Table 2 (continued ) Drugs/medical illnesses Antimigraine First-line agents Acetaminophen Metoclopramide Second-line agents Acetaminophen codeine Acetaminophen caeine Opioids Selective serotonin agonists Contraindicated NSAIDs O 48 hours

Antiparasitic Antipsoriatic Antipsychotic

Lindane 1% Permethrin 5% Calcipotriene Cyclosporin A Haloperidol

Retin-A derivatives Methotrexate sodium Clozaril Zyprexa Seroquel Risperdal Valacyclovir Famciclovir Rifampin Ethambutol Pyrazinamide Benzodiazepines

Antiviral Antitubercular

Acyclovir Isoniazid

Streptomycin

Anxiolytics

Bronchitis

Chemotherapeutics Constipation

Buspirone Zolpidem Antihistamines Acetaminophen Decongestants Cough suppressants Contraindicated Psyllium

Antibiotics

Gastroesophageal reux Hemorrhoids

Antacids

Lactulose Sorbitol Glycerin Rantidine Lansoprazole Pantoprazole

Immunosuppressants

Psyllium Hydrocortisone suppositories Glucocorticoids Azathioprine Cyclosporin Tacrolimus 5-aminosalicylic acid

Mycophenolate mofetil Sirolimus Cyclophosphamide Leunomide Sulfasalazine Corticosteroids Metronidazole Antibiotics

Inammatory bowel

Inuenza

Acetaminophen Decongestants Cough suppressants

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1234 Table 2 (continued ) Drugs/medical illnesses Intrahepatic cholestasis Mood stabilizers Pneumonia

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First-line agents Antihistamines Ursodeoxycholic acid Cholestyramine Lamotrigine Acetaminophen Erythromycin Azithromycin Ceftriaxone Methadone

Second-line agents Phenobarbital

Contraindicated

Valproate Carbamazepine

Polysubstance abuse Ethanol Tobacco Heroin Respiratory infection Upper respiratory Sinusitis

Vasomotor rhinitis

Acetaminophen Decongestants Amoxicillinclavulanate Cefuroxime Saline nasal spray Steroid nasal spray Saline nasal spray Ipratropium Steroid nasal spray

Benzodiazepines Buprenorphine Nicotine replacement Bupropion Cough suppressants Ipratropium

Antabuse

Abbreviation: NSAIDs, nonsteroidal anti-inammatory drugs.

The FDA dened ve risk categories (A, B, C, D, X) that are used by manufacturers to rate their products for use during pregnancy. The approximate frequency of medication in each risk category is 2% for A, 50% for B, 38% for C, 3% to 5% for D, and 1% to 5% for X [3]. Ratings range from A for drugs that show no evidence of damage to the fetus, to D and X for drugs that are denitely teratogenic. The D rating is generally reserved for drugs (eg, secobarbital, doxycycline, lorazepam) with no safer alternatives. The X rating means there is absolutely no reason to take the drug in pregnancy (eg, oral contraceptives, benzodiazepines, misoprostol). These FDA categories are outdated, however, and often do not reect the degree to which available information has ruled out risk to the fetus. A major initiative is underway to make these categories obsolete and provide more informative drug labeling for clinicians and their pregnant patients. Pregnancy labels of the future likely will address three important areas: (1) clinical considerations, (2) summary risk assessment, and (3) data to support the assessment. The goals of the initiative are to highlight clinical considerations relevant to making prescribing decisions for a particular medication for pregnant women, including disease risk and the risk of no treatment. This label also will include information that may assist

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clinicians when counseling women whose fetuses are inadvertently exposed to medications in early gestation. The summary risk assessment section may be a narrative text that articulates, as best can be determined, the risk of exposure based on animal and human data. Fetal eects from specic medications We compiled a list in Table 2 of rst-line, second-line, and contraindicated agents in treating medical illnesses during pregnancy. A drug was selected as being rst line if there had been much clinical experience to be considered safe or if the reported experience was sucient to suggest no additional risk. Table 3 describes fetal eects from drugs listed in Table 2 as being contraindicated. Most human data involve small series or case reports that, although helpful, may be biased or reect the pregnancys background risk for birth defects. Case reports of malformations after prenatal exposure to a certain drug may include exposures to other agents and a lack of uniformity of abnormalities, which makes their association with a single agent unlikely.
Table 3 Examples of contraindicated drugs and their known adverse eects on the developing human fetus Drugs ACE inhibitors Antabuse Chemotherapeutics Doxycycline I-131 Immunosuppressants Mycophenolate mofetil Sirolimus Cyclophosphamide Leunomide Live-attenuated virus Methotrexate NSAIDs Quinolones Retin-A derivatives Streptomycin Tetracycline Thalidomide Warfarin First-trimester fetal eects Cardiac/CNS malformations Congenital malformations Abortion, anomalies Fetal thyroid development Embryopathy Same as above Same as above Same as above Embryopathy IUGR, miscarriage, cranial anomalies Cardiac, gastroschisis, miscarriage Toxic to developing cartilage CNS, cardiac, facial anomalies Otoxicity None known Limb reduction (gastrointestinal/ cardiac/renal defects) Skeletal defects Second- and third-trimester fetal eects Oligohydramnios, IUGR, renal failure Hypoplastic gonads, IUGR Eect on bone growth CNS development

Same as above Premature ductal closure Toxic to developing cartilage Stillbirth, mental retardation None known Staining of teeth

CNS defects/microhemorrhages

Abbreviations: CNS, central nervous system; IUGR, intrauterine growth restriction; NSAIDs, nonsteroidal anti-inammatory drugs.

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Principles of maintenance drug therapy are the same as in the nonpregnant state. Knowledge about one or two medications for each disorder is recommended. Certain drugs may need to be prescribed either in a higher dose or more frequently to obtain therapeutic concentrations in the expanded intravascular volume during pregnancy. Side eects from medications, such as nausea, fatigue, and gastrointestinal disturbance, may mimic symptoms from physiologic changes during pregnancy. For most drugs, typical doses are not anticipated to increase the risk of congenital anomalies. Dissimilarities in the dose and the route of delivery also limit interpretation. For example, short-term administration of a drug given intravenously or sublingually makes it dicult to relate risk when the same medication is taken orally or vaginally in a lower dose either for a longer period or at a different period of gestation. Randomized controlled trials of drugs are rare during pregnancy, and prospective cohort investigations are uncommon. Because a control population is often not possible, it is also dicult to separate any additional risk from the medication and the underlying disease. Care of gravid women with signicant medical problems should include an assessment of the potential risk not only to the fetus but also to the patients. Occasionally, alternative therapies exist that may be safer to a developing fetus. Although the lowest eective dose is to be prescribed, inadequate treatment may lead to minimal benet and potentially greater risk to the pregnancy. Although information about prescription drug use is often scant, assessing risks associated with over-the-counter medications and natural food products is even more dicult. It should be emphasized, however, that these medications should be taken as directed by the product label. A review of the PDR for Non-Prescription Drugs reveals little or no information about reproductive hazards for most of these medications [7]. Many agents contain multiple ingredients, both active and inactive, which compounds counseling about pregnancy risks. Doses may not be included in the product labeling, although the dose is usually low. Summary Medications are taken during gestation at the same frequencydor more oftendas before pregnancy. Testing to assess overall fetal well-being is not predictive of a drugs eects. Few drugs are major teratogens during early gestation, but heightened vigilance is crucial to protect pregnant patients. Detrimental eects can occur beyond the critical embryo stage as cells continue to divide in the developing hematologic, reproductive, and central nervous systems. Listed in this article are medications believed to be rst line, second line, or contraindicated in treating pregnant women for certain illnesses. In general, when prescribing medications during pregnancy, the primary care physician should typically follow the same principles as for a nonpregnant patient.

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References
[1] Splinter M, Nightingale B, Sawgraves R, et al. Medication use during pregnancy by women delivering at a tertiary university hospital. South Med J 1997;90:498502. [2] American College of Obstetricians and Gynecologists. Teratology. ACOG Educ Bull 1997; 236:8779. [3] Physicians desk reference. 62nd edition. Montvale (NJ): Medical Economics; 2008. [4] Briggs GG, Freeman RK, Yaee FJ. Drugs in pregnancy and lactation: reference guide to fetal and neonatal risk. 7th edition. Baltimore (MD): Williams & Wilkins; 2005. [5] Briggs GG, Freeman RK, Yaee FJ. ReproTox database, vol. 13, no. 1. Bethesda (MD): Reproductive Toxicology Center; 2000. [6] ReproTox. Bethesda, MD, Reproductive Toxicology Center. Available at: http://reprotox. org/. Accessed January 24, 2008. [7] PDR for nonprescription drugs. 29th edition. Montvale (NJ): Medical Economics; 2008.